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Principal Investigator: Wasif A Osmani
Organization: MEDICAL COLLEGE OF WISCONSIN
Fiscal Year: 2024
Award: $51,064
Funding agency: National Heart Lung and Blood Institute
Abstract: Epilepsy is one of the most common neurological conditions in the world. Treatment with anti-epileptic
drugs (AEDs) prevent recurrent seizures in ~70% of patients with epilepsy, but the remaining 30% of patients
with refractory epilepsies continue to experience uncontrolled seizures. The negative consequences of repeated
seizures include post-ictal cardiorespiratory suppression putting these patients at high risk of Sudden
Unexpected Death in Epilepsy (SUDEP). Fundamental knowledge gaps exist in our understanding of how
repeated seizures disrupt the vital cardiorespiratory control systems in the brain. A factor commonly identified in
many neurological conditions including epilepsy is neuroinflammation, which supports beneficial functions in
health but is dysregulated in epilepsy patients and animal models of seizure disorder. Key cells within the CNS
mediating pathological neuroinflammation are resident microglia and astrocytes, which have also been shown
to be dysfunctional in human epilepsy. However, it is not known what mechanistic role the glial-derived
neuroinflammation plays in the impairment of cardiorespiratory control or increased SUDEP risk. Here, I
hypothesize that repeated seizures lead to activation of neuroinflammation mediated by microglia within
key brainstem regions controlling cardiorespiratory function causing a progressive decline in these vital
functions. Published and preliminary data in our novel rat model with genetic mutations in a gene (kcnj16)
encoding an inwardly-rectifying potassium ion channel (Kir5.1; SSkcnj16-/- rats) show that repeated sound-induced
seizures (1/day for up to 10 days) lead to progressively more severe post-ictal cardiorespiratory suppression and
unexpected mortality particularly in male rats. Through snRNA sequencing and bioinformatic pathway analyses
of transcriptomic changes specifically within microglial cells in the medullary raphe (key breathing control region)
identified significant predicted activation of IL-1ß signaling following repeated seizures, consistent with
immunofluorescent brainstem tissue analyses. Here I propose two Specific Aims which: 1) characterize cell-
specific transcriptomic shifts in gene expression within key cardiorespiratory control regions to identify key cells
types and pathways mediating local neuroinflammation leading to neuronal dysfunction, and 2) functionally test
the roles of microglia and IL-1 signaling in the brain in mediating the progressive cardiorespiratory suppression
and/or unexpected seizure-induced mortality. Identifying neuroinflammatory signals/pathways induced by
repeated seizures within distinct neural circuits in our novel rat model will enhance our understanding of the
pathophysiological consequences of uncontrolled seizures in patients with refractory epilepsy, and hold the
potential for identifying new therapeutic targets aimed at preventing seizure-induced cardiorespiratory
dysfunction function and reduce SUDEP risk.
Terms: <5-HT><5-Hydroxytryptamine><5HT><Address><Affect><Ammon Horn><Animal Model><Animal Models and Related Studies><Anti-epileptic><Apnea><Architecture><Assay><Astrocytes><Astrocytus><Astroglia><Astroprotein><Asystole><B-Cell Attracting Chemokine 1><B-Lymphocyte Chemoattractant><BCA1><BLC gene><BLC protein><BLR1><BLR1 gene><Baroreceptor Reflex><Baroreflex><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Body Tissues><Brain><Brain Nervous System><Brain Stem><Brain region><Brainstem><Breathing><CCL2><CCL2 gene><COX-2><COX2><CXCL13><CXCL13 gene><CXCR-5><CXCR5><Cardiac Arrest><Cardiac Chronotropism><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Cessation of life><Chemokine Receptor Gene><Chemokine, CC Motif, Ligand 2><Chemokine, CXC Motif, Ligand 13><Chemoreceptors><Chemotactic Cytokines><Chronic><Common Rat Strains><Cornu Ammonis><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Death><Differential Gene Expression><Dysfunction><Encephalon><Engineering / Architecture><Enteramine><Epilepsy><Epileptic Seizures><Epileptics><Esteroproteases><Event><Exons><Exposure to><Expression Signature><Failure><Fellowship><Female><Functional disorder><GFA-Protein><GFAP><Gene Expression><Gene Expression Profile><Generations><Genes><Genetic mutation><Glial Fibrillary Acid Protein><Glial Fibrillary Acidic Protein><Glial Intermediate Filament Protein><Goals><Health><Heart Arrest><Heart Rate><Hippocampus><Hippophaine><Homologous Chemotactic Cytokines><Hortega cell><Human><IL-1><IL1><IL1R><IL1R1><IL1R1 gene><IL1RA><IRK1 channel><Impairment><Individual><Inflammatory><Inpatients><Intercrines><Interleukin I><Interleukin-1><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intractable Epilepsy><Inward Rectifier K+ Channels><Inwardly Rectifying K+ Channels><Inwardly Rectifying Postassium Channels><Inwardly Rectifying Potassium Channels><K channel><Knock-out><Knockout><Knowledge><Lead><Life><Ligands><Lymphocyte-Stimulating Hormone><MCAF><MCP-1><MCP1><MDR15><Macrophage Cell Factor><Mediating><Mediator><Medical><Microglia><Modeling><Modern Man><Molecular><Monitor><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Morphology><Nerve Cells><Nerve Degeneration><Nerve Unit><Network Analysis><Neural Cell><Neurocyte><Neurologic><Neurological><Neuron Degeneration><Neuronal Dysfunction><Neurons><Nuclear RNA><Nucleus><Nucleus Tractus Solitarii><Nucleus solitarius><PGHS-2><PHS-2><PTGS2><PTGS2 gene><Pathologic><Pathway Analysis><Pathway interactions><Patients><Pattern><Pb element><Peptidases><Peptide Hydrolases><Persons><Physiopathology><Play><Potassium Channel><Potassium Ion Channels><Prevention><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Protocol><Protocols documentation><Publishing><RNA Seq><RNA sequencing><RNAseq><Rat><Rats Mammals><Rattus><Receptor Protein><Recurrence><Recurrent><Refractory epilepsy><Respiratory Aspiration><Respiratory Inspiration><Respiratory physiology><Risk><Rodent Model><Role><SCYA2><SCYB13><SIS cytokines><SUDEP><Seizure Disorder><Seizures><Sequence Alteration><Serotonin><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single-Nucleus Sequencing><Small Inducible Cytokine A2><Small Inducible Cytokine Subfamily B, Member 13><Solitary Nucleus><System><T Helper Factor><Testing><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Tissues><Tonic - clonic seizures><ZNFs><Zn-finger nuclease><anti-epileptic agents><anti-epileptic drugs><astrocytic glia><audiogenic seizure><biological signal transduction><cell type><chemoattractant cytokine><chemokine><chemokine receptor><cytokine><drug-resistant epilepsy><epilepsia><epileptogenic><experience><experiment><experimental research><experimental study><experiments><gene expression pattern><gene expression signature><genomic alteration><gitter cell><glial activation><glial cell activation><grand mal seizure><hCOX-2><heavy metal Pb><heavy metal lead><high risk><hippocampal><human data><inspiration><interventional strategy><inward rectifier potassium channel><lymphocyte activating factor><male><mesoglia><microglial cell><microgliocyte><model of animal><mortality><neural circuit><neural circuitry><neural degeneration><neural dysfunction><neural inflammation><neural network><neurocircuitry><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathophysiology><pathway><patient population><perivascular glial cell><pharmacologic><preBotzinger complex><prevent><preventing><raphe nuclei><receptor><receptor function><respiratory><respiratory function><sNuc-Seq><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><solitary tract nucleus><sound><sudden unexpected death in epilepsy><synaptic circuit><synaptic circuitry><transcriptional profile><transcriptional signature><transcriptome profiling><transcriptome sequencing><transcriptomic profiling><transcriptomic sequencing><transcriptomics><zinc finger nuclease><zinc finger nucleases>